Novel BRAF Fusions Identified in 'Pan-Negative' Melanomas
A study by Sosman et al has identified two novel BRAF fusions in melanomas previously considered to be negative for molecular targets. In addition, these “pan-negative” melanomas were found to be sensitive to MEK inhibitors. According to the study, BRAF fusions define a new molecular subset of melanoma, potentially comprising between 4% and 8% of pan-negative cases. The study is published in Clinical Cancer Research.
The researchers used the FoundationOne platform to perform next-generation sequencing analysis on a melanoma sample from one of their patients and identified a fusion between two genes, PAPSS1 and BRAF, which they called PAPSS1-BRAF, in a pan-negative melanoma. They then analyzed melanomas from an additional 51 patients, 24 of which were pan-negative. In one of the pan-negative samples, the researchers identified a second novel BRAF fusion, TRIM24-BRAF.
“About 35% of melanomas are, as of today, considered pan-negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11,” said study author Jeffrey A. Sosman, MD, Professor of Medicine at Vanderbilt-Ingram Cancer Center, in a statement. “We have been interested in looking at patients whose tumors have none of these driver mutations to see what their tumors do have that can be targeted therapeutically.”
Study Findings
Additional studies in the laboratory revealed that both BRAF fusions activated the mitogen-activated protein kinase (MAPK) signaling pathway in the cancer cells. The investigators then treated these fusion-bearing cells with either the BRAF inhibitor vemurafenib (Zelboraf) or trametinib (Mekinist), which inhibits MEK, a protein in the MAPK signaling pathway. They found that signaling induced by the BRAF fusions was not responsive to vemurafenib but could be inhibited by trametinib, leading them to conclude that the novel fusions they identified could make melanoma cells harboring them responsive to MEK inhibitor therapies or assist in selecting patients for MEK-directed therapy.
“Currently, there is immense value in identifying novel mutations in untreatable cancers because many of them are clinically relevant, which means they may be sensitive to drugs that are either being developed or are already FDA approved,” said Dr. Sosman in a statement. “Our data support the idea that 'pan-negative' cancers are not truly pan-negative.”
The study authors concluded, “Collectively, these biochemical and genetic data define an additional molecular subset of melanoma that should be routinely screened for in the clinic, and knowledge about BRAF fusions in melanoma may provide insights into the mechanism of responses to treatment with an expanding list of available kinase inhibitors.”
Dr. Sosman and William Pao, MD, PhD, of Vanderbilt-Ingram Cancer Center, are the corresponding authors for the Clinical Cancer Research article.
The study was funded by the Stand Up To Cancer Melanoma Dream Team, the James C. Bradford Family Foundation, the American Cancer Society, the National Cancer Institute, a Stand Up To Cancer Innovative Research Grant, and the Joanna M. Nicolay Melanoma Foundation 2013 Research Scholar Award. Dr. Sosman is on the advisory board for GlaxoSmithKline PLC.
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